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An intense lifestyle intervention for patients with type 2 diabetes that was focused on diet and exercise failed to protect patients against heart problems.

Note that weight loss was greater in the intervention group than in the control group throughout the study.

CHICAGO -- An intense lifestyle intervention for patients with type 2 diabetes that was focused on diet and exercise failed to protect patients against heart problems, researchers reported here.

Final analysis of the randomized, controlled Look AHEAD trial, which was halted in September for failing to show cardiovascular benefit, revealed no significant differences in a composite of cardiovascular endpoints between those who had the intervention and those who only received advice (1.83 events per 100 person-years versus 1.92, P=0.51), according to Rena Wing, PhD, of Brown University, and colleagues.

They reported their findings simultaneously online in the New England Journal of Medicine and at the American Diabetes Association meeting here.

Wing said during a press briefing that there are a host of explanations for the lack of benefit, among them the fact that participants in the control group were on more medications, particularly statins, which could have lowered their risk of cardiovascular disease, and they also received good education on their disease and on lifestyle.

Also, Wing and colleagues noted, the weight loss achieved by those in the intense group may not have been sufficient to reduce the risk of cardiovascular disease; or the education received in the control group could have lessened the difference between the two groups.

Regardless of the lack of overall cardiovascular benefit, Wing said, the trial was valuable in that it showed patients with diabetes "can lose weight and maintain that weight loss. This weight loss has many beneficial effects on glycemic control and cardiovascular risk factors."

"It just doesn't affect the risk of cardiovascular disease," she said during a press briefing.

Smaller and shorter-term studies have shown that weight loss can improve cardiovascular disease risk factors for obese and overweight patients who have type 2 diabetes, but the long-term effects on hard cardiovascular endpoints such as MI and death have not been well studied.

Close-up Look at the Trial

Wing and her colleagues initiated the Look AHEAD (Action for Health in Diabetes) trial to assess those endpoints, enrolling 5,145 overweight or obese patients with type 2 diabetes at 16 centers in the U.S.

The patients were randomized to either an intensive lifestyle intervention that focused on weight loss through decreased caloric intake and increased physical activity, or to a control group that received only education about their disease.

Mean age of participants was 58.7, mean body mass index (BMI) was 36, the median duration of diabetes was 5 years, and 14% had a history of cardiovascular disease.

The primary outcome was a composite of death from cardiovascular causes, nonfatal MI, nonfatal stroke, and hospitalization for angina.

When the trial was stopped in September 2012, the median follow-up time was 9.6 years.

Wing and colleagues saw greater weight loss in the intervention group than among controls at one year (8.6% versus 0.7%) but that gap started to close toward the end of the study given that initial weight loss was followed by weight regain through year five and, thereafter, a subsequent gradual drop in weight (6% versus 3.5%).

Control patients had gradual but consistent weight loss throughout the study.

The intense lifestyle change also led to greater reductions in glycated hemoglobin (HbA1c) at one year, as well as greater initial improvements in fitness and all cardiovascular risk factors, except for LDL cholesterol at that time.

These between-group differences diminished over time, however, although HbA1c and systolic blood pressure showed the most sustained differences.

The use of antihypertensives, statins, and insulin was also lower in the intervention group than in the control group.

The primary composite outcome occurred in 403 patients in the intervention group and 418 in the control group, which did not translate to a significant difference (1.83 versus 1.92 events per 100 person-years, P=0.51).

Nor were there any significant differences between groups in terms of secondary composite outcomes or any of the individual cardiovascular events making up those outcomes.

With regard to adverse events, the rate of self-reported fractures was significantly higher in the intervention group (2.51 versus 2.16 per 100 person-years, P=0.01), but there were no significant differences in the rate of adjudicated fractures, they reported (1.66 and 1.64 per 100 person-years, respectively).

Wing noted that subgroup analyses looking at outcomes by history of cardiovascular disease didn't turn up any significant findings, but they did show "some suggestion" that the intervention was effective at reducing the risk of cardiovascular disease in patients without a history of heart problems.

"We are interested in following Look AHEAD participants over time to see if this nonsignificant effect increases or decreases over time," Wing said during the briefing. "I think that will be one of the important things to follow over time."

The study was limited because patients self-selected to enter the trial, so the findings may not generalize to all patients, particularly those who are less motivated. Also, it's unclear if other intense interventions, such as one that focused on dietary composition, may lead to different outcomes.

Still, the researchers concluded, the findings "must be considered in the context of other positive effects observed with this intervention," particularly the changes in HbA1c.

Study Did Show Other Benefits

During the meeting, other investigators in the Look AHEAD trial reported data from other analyses.

William Knowler, MD, PhD, MPH, of the National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK), said the intervention was associated with less kidney disease over 10 years, with a 31% lower annual rate of development for those in the intensive lifestyle management group.

He and his colleagues also found a 14% lower risk of retinopathy with the intervention, but there was no significant difference between groups in terms of neuropathy.

Lucy Faulconbridge, PhD, of the University of Pennsylvania, reported a 20% lower risk of depression over the trial period for participants in the lifestyle group. Rates of incident diabetes were 17.5% for those in the intervention group compared with 21% for those in the control group.

Remission rates were the same over the course of the trial, however, and there were no differences between groups in the incidence of use of antidepressants, she said.

There was a 3.1% difference between overall health-related quality of life between groups over the course of the study, but mental health-related quality of life was not different between the two.

Finally, Henry Glick, PhD, also of the University of Pennsylvania, presented data on cost-efficacy, noting that an 11.9% reduction in hospitalizations for the intensive lifestyle management group translated to an average savings of $294 per year and a $2,610 savings in discounted dollars over 10 years.

Also, a 6.3% reduction in medications translated to an annual savings of $278 per year and a $2,487 savings in discounted dollars over 10 years.

In an accompanying editorial, Hertzel Gerstein, MD, of the University of Hamilton in Ontario in Canada, wrote that the findings "may mean that lifestyle interventions do not effectively reduce the rate of cardiovascular events in patients with type 2 diabetes."

But Gerstein also noted that any differences could have been diminished by reduced use of cardioprotective drugs in the intervention group, and by the fact that the effects of the intervention on weight loss and other risk factors waned after the first few years.

And using hospitalization for angina as part of the composite endpoint "may have added noise and further obscured any emerging signal," given that the incidence of angina was nearly identical in the two groups, while all other endpoints numerically favored the intervention group.

Gerstein concluded that from the results of Look AHEAD, clinicians can "clearly assert that changes in activity and diet safely reduce weight and reduce the need for and cost of medications."

The study was supported by the NIH. Additional support was provided by several universities and by FedEx, Health Management Resources, Johnson & Johnson, Nestle HealthCare Nutrition, Hoffman-La Roche, Abbott Nutrition, and Unilever North America.

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